The present invention relates to the use of the compound 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4xe2x80x2-piperidine] or a pharmaceutically acceptable salt thereof for the preparation of medicaments for the treatment of depression.
International Patent Publication No. WO 92/22554 describes a series of sigma receptor ligands considered useful for the treatment of a range of psychic and neurological disorders. The structure activity relationship of these compounds has been further investigated by Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, p. 1998-2008.
Among numerous other compounds, said patent publication discloses the compound 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H)4xe2x80x2-piperidine] 
which is the subject of the present invention. This compound was shown in Perregaard, J. et al., J Med. Chem., 1995, 38, 11, p. 1998-2008 to be a potent and selective sigma ligand, in particular a sigma2 ligand. Furthermore, the anxiolytic potential of the compound was tested in the black/white exploration test in rats, which is an animal model predictive for effect in the treatment of generalised anxiety disorder. It was found to be active over a large dose range. Results of further tests in generalised anxiety disorder models are reported in J Pharmacol. Exp. Ther., 1997, 283, No. 2.
Co-pending Danish patent applications Nos. 1267/97, 0071/98 and 0501/98 relate to the hydrochloride of the compound, the effect of the compound in the treatment of addiction to drugs and other substances of abuse and the use of the compound in the treatment of panic attacks, respectively.
Evidence has been presented from studies of the biology and function of sigma receptors that sigma receptor ligands may be useful in the treatment of a range of psychic and neurological disorders, including psychosis and movement disorders, such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington""s chorea or Tourette""s syndrome and in Parkinson""s disease (Walker, J. M. et al, Pharmacological Reviews, 1990, 42, 355). The known sigma receptor ligand, rimcazole, clinically shows effect in the treatment of psychosis (Snyder, S. H., Largent, B. L. J Neuropsychiatry, 1989, 1, 7) and a group of sigma receptor ligands have been described to show antihallucinogenic activity in animal models (International Patent Publication No. WO 9103243).
Sigma receptor ligands have also been reported to be involved in modulation of NMDA receptor mediated events in the brain and to act as anti-ischemic agents in in vivo tests (Rao, T. S. et al, Molecular Pharmacology, 1990, 37, 978). In addition to ischemia, the sigma receptor ligands may also be useful in the treatment of other such NMDA receptor mediated events, e.g. epilepsy and convulsion.
Also, some sigma receptor ligands have been found to show anti-amnesic effects in an animal model (Early et al., Brain Research, 1991, 546, 281-286). Sigma ligands have been shown to influence central acetylcholine levels in animal models (Matsuno et al, Brain Research, 1992, 575, 315-319; Junien et al, Eur. J. Pharm., 1991, 200, 343-345) and may, therefore, have potential in the treatment of senile dementia of the Alzheimer type.
Finally, some guanidine derivatives having sigma receptor activity have been disclosed to be useful as anxiolytics (International Patent Publication No. WO 9014067) and some sigma receptor ligands have been found to bind to the cocaine binding site on the dopamine transporter and others have been found to inhibit dopamine uptake (Izenwasser, S., et al, Eur. J Pharmacol, 243, 201-205 and Woodward, J. J. and Harms, J., Eur. J Pharmacol., 210, 265-270.
Depression is now well recognised as an extremely damaging and invalidating disorder and it has a very large prevalence. It is often associated with suicidal behaviour and people afflicted have a very low quality of life.
Selective serotonin re-uptake inhibitors are now first choice treatments in depression disorders. However, they are only effective after 3-4 weeks of treatment and they are not effective in all patients.
Consequently, there is a need for alternative therapies useful in the treatment of disorders associated with depression.
It has now, surprisingly, been found that the compound of the invention shows a beneficial effect in the treatment of depression.
According to the present invention, a novel use of 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4xe2x80x2-piperidine], namely for the preparation of a medicament useful in the treatment depression is provided.
The term depression contemplates all diseases and conditions which are associated with depression including those classified in the IDC-10 and DSM-IV rating scales. Such diseases or disorders comprise major depression, dysthymic disorder, depressive episodes of bipolar disorders and depressive episodes associated with other mood disorders, including seasonal mood disorders and mood disorders due to a general medical condition and substance induced mood disorder.
The term xe2x80x9ctreatment of depressionxe2x80x9d covers relief of symptoms, cure or prevention of the disease or condition.
According to the invention, the compound 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4xe2x80x2-piperidine] may be used as the base of the compound or as a pharmaceutically acceptable acid addition salt thereof or as an anhydrate or hydrate of such salt. The salts of the compound used in the invention are salts formed with non-toxic organic or inorganic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Preferably, the compound is used as the base, the hydrochloride or the fumarate.
Chronic administration of the compounds used in the method of the invention has been found to cause a reversal of anhedonia induced by chronic mild stress in rats in the chronic mild stress (CMS) model. The CMS-model is a well recognised model of depression (Willner, Paul, Psycopharmacology, 1997, 134, 319-329.)
According to the invention, 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4xe2x80x2-piperidine], or a pharmaceutically acceptable salt thereof, may be administered in any suitable way such as orally or parenterally, and it may be presented in any suitable form for such administration, for example in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
Methods for the preparation of solid pharmaceutical preparations are well known in the art. Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
The compound of the invention is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 xcexcg/kg to 10 mg/kg body weight, preferably 25 xcexcg/day/kg to 2.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body weight.
The fumarate of 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4xe2x80x2-piperidine] can be prepared as described in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, 1998-2008 (compound 14f) and the base and other pharmaceutically acceptable salts may be obtained therefrom by standard procedures.
Thus the acid addition salts according to the invention may be obtained by treatment of 1xe2x80x2-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4xe2x80x2-piperidine] with the acid in an inert solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and if desired micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process.
Precipitation of the salt is preferably carried out in an inert solvent, e.g. an inert polar solvent such as an alcohol (e.g. ethanol, 2-propanol and n-propanol).